doi:10.

1093/brain/awaa240 BRAIN 2020: 143; 3104–3120 | 3104

The emerging spectrum of COVID-19

neurology: clinical, radiological and
laboratory findings

Downloaded from https://academic.oup.com/brain/article/143/10/3104/5868408 by guest on 30 July 2021

Ross W. Paterson,1,2,3,* Rachel L. Brown,1,4,* Laura Benjamin,5,6 Ross Nortley,1,7
Sarah Wiethoff,1,8 Tehmina Bharucha,9,10,11 Dipa L. Jayaseelan,1,12 Guru Kumar,2
Rhian E. Raftopoulos,13 Laura Zambreanu,1,12 Vinojini Vivekanandam,9 Anthony Khoo,9
Ruth Geraldes,7,14 Krishna Chinthapalli,1,7 Elena Boyd,7 Hatice Tuzlali,7 Gary Price,9
Gerry Christofi,9 Jasper Morrow,1,9 Patricia McNamara,9 Benjamin McLoughlin,9
Soon Tjin Lim,9 Puja R. Mehta,9 Viva Levee,9 Stephen Keddie,1 Wisdom Yong,15
S. Anand Trip,1,15 Alexander J. M. Foulkes,1,12 Gary Hotton,9 Thomas D. Miller,16
Alex D. Everitt,17 Christopher Carswell,17,18 Nicholas W. S. Davies,18 Michael Yoong,19
David Attwell,20 Jemeen Sreedharan,13 Eli Silber,13 Jonathan M. Schott,1
Arvind Chandratheva,5 Richard J. Perry,5 Robert Simister,5 Anna Checkley,21
Nicky Longley,21 Simon F. Farmer,9 Francesco Carletti,22 Catherine Houlihan,9,23
Maria Thom,1 Michael P. Lunn,1 Jennifer Spillane,9,24 Robin Howard,9,24
Angela Vincent,1,14 David J. Werring,5 Chandrashekar Hoskote,22 Hans Rolf Jäger,1,22
Hadi Manji1,9,* and Michael S. Zandi1,9,* for the UCL Queen Square National Hospital for
Neurology and Neurosurgery COVID-19 Study Group

*These authors contributed equally to this work.

Preliminary clinical data indicate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with
neurological and neuropsychiatric illness. Responding to this, a weekly virtual coronavirus disease 19 (COVID-19) neurology
multi-disciplinary meeting was established at the National Hospital, Queen Square, in early March 2020 in order to discuss and
begin to understand neurological presentations in patients with suspected COVID-19-related neurological disorders. Detailed clinic-
al and paraclinical data were collected from cases where the diagnosis of COVID-19 was confirmed through RNA PCR, or where
the diagnosis was probable/possible according to World Health Organization criteria. Of 43 patients, 29 were SARS-CoV-2 PCR
positive and definite, eight probable and six possible. Five major categories emerged: (i) encephalopathies (n = 10) with delirium/
psychosis and no distinct MRI or CSF abnormalities, and with 9/10 making a full or partial recovery with supportive care only;
(ii) inflammatory CNS syndromes (n = 12) including encephalitis (n = 2, para- or post-infectious), acute disseminated encephalomy-
elitis (n = 9), with haemorrhage in five, necrosis in one, and myelitis in two, and isolated myelitis (n = 1). Of these, 10 were treated
with corticosteroids, and three of these patients also received intravenous immunoglobulin; one made a full recovery, 10 of 12
made a partial recovery, and one patient died; (iii) ischaemic strokes (n = 8) associated with a pro-thrombotic state (four with pul-
monary thromboembolism), one of whom died; (iv) peripheral neurological disorders (n = 8), seven with Guillain-Barré syndrome,
one with brachial plexopathy, six of eight making a partial and ongoing recovery; and (v) five patients with miscellaneous central
disorders who did not fit these categories. SARS-CoV-2 infection is associated with a wide spectrum of neurological syndromes
affecting the whole neuraxis, including the cerebral vasculature and, in some cases, responding to immunotherapies. The high inci-
dence of acute disseminated encephalomyelitis, particularly with haemorrhagic change, is striking. This complication was not

Received June 1, 2020. Revised June 29, 2020. Accepted June 30, 2020. Advance access publication July 8, 2020
C The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse,
distribution, and reproduction in any medium, provided the original work is properly cited.
The emerging spectrum of COVID-19 neurology BRAIN 2020: 143; 3104–3120 | 3105

related to the severity of the respiratory COVID-19 disease. Early recognition, investigation and management of COVID-19-related
neurological disease is challenging. Further clinical, neuroradiological, biomarker and neuropathological studies are essential to de-
termine the underlying pathobiological mechanisms that will guide treatment. Longitudinal follow-up studies will be necessary to
ascertain the long-term neurological and neuropsychological consequences of this pandemic.

1 University College London, Queen Square Institute of Neurology, London, UK

2 Darent Valley Hospital, Dartford, Kent, UK
3 UK Dementia Research Institute, London, UK
4 UCL Institute of Immunity and Transplantation, London, UK
5 Stroke Research Centre, UCL Queen Square Institute of Neurology, London, UK
6 University of Liverpool, Brain Infections Group, Liverpool, Merseyside, UK
7 Wexham Park Hospital, Frimley Health NHS Foundation Trust, Berkshire, UK
8 Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, Tübingen, Germany

Downloaded from https://academic.oup.com/brain/article/143/10/3104/5868408 by guest on 30 July 2021

9 National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square,
London, UK
10 Department of Biochemistry, University of Oxford, Oxford, UK
11 Lao-Oxford-Mahosot Hospital-Wellcome Trust-Research Unit, Mahosot Hospital, Vientiane, Laos
12 Watford General Hospital, Watford, Hertfordshire, UK
13 King’s College Hospital, Denmark Hill, London, UK
14 University of Oxford, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK
15 Northwick Park Hospital, Harrow, London, UK
16 Lister Hospital, Stevenage, Hertfordshire, UK
17 Imperial College Healthcare NHS Trust, London, UK
18 Chelsea and Westminster Hospital, London, UK
19 Barts and The London NHS Trust, London, UK
20 UCL, Department of Neuroscience, Physiology and Pharmacology, London, UK
21 Hospital for Tropical Diseases, University College London Hospitals NHS Foundation Trust, London, UK
22 Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, University College London Hospitals
NHS Foundation Trust, Queen Square, London, UK
23 UCL Division of Infection and Immunity, London, UK
24 Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Correspondence to: Dr Michael S. Zandi, PhD FRCP

University College London Queen Square Institute of Neurology
London WC1N 3BG
UK
E-mail: m.zandi@ucl.ac.uk

Keywords: COVID-19; SARS-CoV-2; encephalitis; ADEM

Abbreviations: ADEM = acute demyelinating encephalomyelitis; COVID-19 = coronavirus disease 19; GBS = Guillain-Barré syn-
drome; IVIG = intravenous immunoglobulin; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2

syndrome (GBS) (Toscano et al., 2020). Radiological series

Introduction
Since December 2019, almost 10 million cases and 500 000
deaths due to the novel coronavirus, severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2), have been reported
worldwide (WHO situation report). Although the
respiratory system complications of coronavirus disease 19
(COVID-19) have been the most frequent and life threaten-
ing, there are increasing reports of central and peripheral
nervous system (PNS) involvement. These neurological com-
plications have included encephalopathy (Helms et al.,
2020), meningo-encephalitis (Moriguchi et al., 2020), ischae-
mic stroke (Beyrouti et al., 2020), acute necrotizing enceph-
alopathy (Poyiadjin et al., 2020), and Guillain-Barré
have shown infarcts, microhaemorrhages, features of poster-
ior reversible encephalopathy syndrome, or nerve root en-
hancement (Franceschi et al., 2020; Mahammedi et al.,
2020). Zanin and colleagues (2020) have described a case
of CNS demyelination post-COVID-19. Detailed neuro-
logical assessment and investigation is challenging in
those who are critically ill, limiting the opportunity to de-
lineate the underlying pathophysiology and hence, treat-
ment options. The postulated mechanisms of the various
neurological syndromes include, either individually or in
combination, direct viral neuronal injury (Zubair et al.,
2020), a secondary hyperinflammation syndrome (Mehta
et al., 2020), para- and post-infectious inflammatory or
3106 | BRAIN 2020: 143; 3104–3120
immune-mediated disorders, or the effects of a severe
systemic disorder with the neurological consequences of
sepsis, hyperpyrexia, hypoxia, hypercoagulability and
critical illness.
Here we describe the detailed emerging spectrum of neuro-
logical disorders encountered in 43 COVID-19 patients
referred to the National Hospital, Queen Square COVID-19
multidisciplinary team meeting (COVID-MDT), run in part-
nership with infectious disease and virology colleagues at
University College London Hospital (UCLH).
Materials and methods
We reviewed retrospectively the clinical, radiological, laboratory
and neuropathological findings from patients referred to the
COVID-MDT neurology/encephalitis and neurovascular multi-
disciplinary team meetings. The cases summarized were
discussed between 9 April and 15 May 2020. Neurological
syndromes developing after definite, probable or possible
COVID-19, which were likely to be associated with COVID-19
on clinical grounds, were included. Cases for which a more like-
ly alternative pathology was found were excluded.
The probability of COVID-19-related neurological disease
was determined using WHO criteria [‘Global surveillance for
human infection with coronavirus disease (COVID-19)’]: (i) def-
inite (SARS-CoV-2 RNA PCR positive from nasopharyngeal
swab, CSF or pathological specimen); (ii) probable (clinical and
laboratory features highly suggestive of COVID-19: lymphope-
nia, raised D-dimer, suggestive chest radiology in the absence of
PCR evidence) (Guan et al., 2020); and (iii) possible, in whom
temporal or laboratory features indicate an association but an-
other cause was also found (Ellul et al., 2020).
The classification of the severity of COVID-19 infection was
adapted from Wu and McGoogan (2020). Mild disease included
patients with non-pneumonia or mild pneumonia, severe disease
included patients with dyspnoea and hypoxia requiring supple-
mentary oxygen, and critical disease included patients with re-
spiratory failure requiring assisted ventilation, septic shock, and/
or multi-organ dysfunction. Where possible, laboratory results
shown are those nearest to onset of neurological symptoms.
Consensus clinical criteria were used to classify individuals with
specific neurological syndromes including encephalitis (Solomon
et al., 2012; Graus et al., 2016), acute demyelinating encephalo-
myelitis (ADEM) (Pohl et al., 2016), and GBS (Willison et al.,
2016). We obtained assent and/or written consent from patients
or from their relatives. This on-going study is approved and reg-
istered as a service evaluation of our MDT (ref 06–202021-SE)
at University College London Hospitals NHS Trust.
Some patient details have been submitted for publication as
case reports by their treating physicians: Patient 7 (Lim et al.,
submitted for publication), Patient 11 (Khoo et al., 2020),
Patient 12 (Zambreanu et al., 2020), Patient 15 (Dixon et al.,
2020), Patients 23, 24, 26, 28, 29 (Beyrouti et al., 2020), and
Patient 41 (Wilson et al., 2020).
Data availability
The data that support the findings of this study are available
from the corresponding author, upon reasonable request. The
data are not publicly available due to ethical restrictions e.g.
R. W. Paterson et al.
their containing information that could compromise the privacy
of the patients reported.
Results
The patients included 24 males and 19 females with ages
ranging from 16 to 85 years. Twenty-three of our patients
(53%) were non-white. Based on a positive nasal-pharyngeal
throat SARS-CoV-2 PCR test, 29 were defined as definite
COVID-19, eight were probable and six were possible for
this association. The severity of the COVID-19 symptoms
varied from mild to critical. The patients presented with a
wide range of CNS and PNS features including neuroinflam-
Downloaded from https://academic.oup.com/brain/article/143/10/3104/5868408 by guest on 30 July 2021
matory diseases and stroke from 6 days before and up to 27
days following the onset of the COVID-19 symptoms. The
patients are divided into five categories based on their clinic-
al, neuroradiological, neurophysiological and laboratory fea-
tures, as summarized in Table 1. We provide a brief
summary of the neurological phenotypes in Tables 2–4. Full
details of the clinical, viral, immunological, radiological and
neurophysiological investigations, management and treat-
ment responses are detailed in the Supplementary material.
CNS syndromes
Encephalopathies
The 10 patients described (Patients 1–10, six female, four
male; four White, five Black and one Asian) had a para-in-
fectious or septic encephalopathy with delirium. These
patients (e.g. Vignette A) were mostly 450 years old and
presented with confusion and disorientation, with psychosis
in one, and seizures in another. Neuroimaging was within
normal limits, and CSF studies were normal when per-
formed. Treatments were largely supportive with 7 of 10
making a complete recovery, and 2 of 10, a partial recovery
at the time of discharge (Table 2 and Supplementary
material).
Vignette A: acute para-infectious encephalopathy
with psychosis
A 55-year-old female (Patient 7), with no previous psychi-
atric history, was admitted with a 14-day history of fever,
cough, muscle aches, breathlessness, as well as anosmia and
hypogeusia. She required minimal oxygen treatment (oxygen
saturation 94% on room air) and was well on discharge 3
days later. The following day, her husband reported that she
was confused and behaving oddly. She was disorientated
and displayed ritualistic behaviour such as putting her coat
on and off repeatedly. She reported visual hallucinations,
seeing lions and monkeys in her house. She developed on-
going auditory hallucinations, persecutory delusions, a
Capgras delusion and complex systematized delusional mis-
perceptions. She displayed intermittently aggressive behav-
iour with hospital staff and her family. Her psychotic
symptoms persisted after disorientation improved. Brain
MRI, EEG and lumbar puncture were normal. Her clinical
Table 1 Summary of clinical features of 43 patients with neurological complications of COVID-19

Cases Age, median Days of COVID-19 Main clinical Results of note % Naso- CSF or brain Treatment Clinical outcome
[range]; %male infection before features pharyhgeal SARS-CoV-2
neurological SARS-CoV-2 PCR +
The emerging spectrum of COVID-19 neurology

presentation, PCR + (x/number

median [range] tested)
Encephalopathy (delirium/ 57.5 [39–72]; 40 4.5 [–4 to + 21] Delirium; psychosis Acellular CSF (6/6); non- 80 (8/10) (0/0) Supportive (9/10); ste- Complete recovery (7/
psychosis) (n = 10)a specific MRI changes roids 1/10 10); partial (2/10)
(3/10)
Inflammatory CNS 53 [27–66]; 33 9 [–6 to + 27] Reduced conscious- Abnormal CSF (6/11) 67 (8/12) (0/7) Corticosteroids (10/ Recovery: complete (1/
syndromes (para-/post- ness (7/12); UMN Abnormal MRI (11/12) 12); IVIG (3/12) 12); partial (10/12);
infectious) (n = 12)a signs (10/12) none (death 1/12)
Stroke (n = 8)a 62.5 [27–85]; 75 8[–2 to + 22] Large vessel ischaemic 4/8 PE 75 (6/8) NA Low molecular weight Incomplete recovery (7/
stroke 6/6 High D–dimer heparin (7/8); apix- 8); death (1/8)
aban (1/8)
Peripheral syndromes (n = 8)
GBS (n = 7) 57 [20–63]; 100 13 [–1 to + 21] Cranial and peripheral 43 (3/7) NT IVIG (7/7) Incomplete recovery (5/
neuropathy 7 GBSDS 2)
Plexopathy (n = 1) 60; 100 14 Painless weakness 100 (1/1) NT IV steroids (1/1) Incomplete recovery (1/
1)
Miscellaneous and unchar- 20 [16–40]; 40 10 [ + 6 to + 26] Raised ICP; seizures; Abnormal CSF (2/4) 60 (3/5) (0/1) Varied (AED; steroids Recovery complete (1/
acterized (n = 5) myelitis Abnormal MRI brain (4/5) (1/5); tLP) 5); partial (3/5); nil (1/
5)

AED = anti-epileptic drug; GBSDS = Guillain Barré disability score; ICP = intracranial pressure; tLP = therapeutic lumbar puncture; NT = not tested; PE = pulmonary thromboembolism; UMN = upper motor neuron.
aFeatures of eight individual patients for encephalopathy (delirium/psychosis), inflammatory CNS syndromes (para/post-infectious) and stroke described in Tables 2–4. All patient details are available in the Supplementary material.
BRAIN 2020: 143; 3104–3120
| 3107

Downloaded from https://academic.oup.com/brain/article/143/10/3104/5868408 by guest on 30 July 2021

 3108

Table 2 Eight patients with spontaneously improving encephalopathies (Patients 1–8)

| BRAIN 2020: 143; 3104–3120

Patient 1 2 3 4 5 6 7 8
Age, M/F, ethnicity, COVID- 65, F, White, definite/ 72, M, White, def- 59, F, Black, defin- 58, M, Black, definite/ 52, F, White, 39, F, Asian, definite/ 55, F, White, definite/ 68, M, Black, defin-
19 diagnosis/severity mild inite/critical ite/mild mild probable/mild critical severe ite/mild
Final neurological diagnosis Hypoactive delirium Hypoactive Delirium Delirium Delirium Delirium Delirium and Hyperactive
delirium psychosis delirium
Initial neurological Fluctuating confusion; Confusion; mal- Fluctuating Confusion; nonsens- Fluctuating con- Delirium; hallucina- Confusion; agitation; Cognitive impair-
symptoms reversal of sleep- aise; loss of confusion ical speech; repeti- sciousness; tions about experi- persecutory delu- ment; gait dis-
wake cycle appetite tive behaviour; delirium ences in countries sions; visual halluci- turbance; two
disorientation; de- not previously vis- nations; combative falls
lusional thoughts; ited; reversed behaviour;
headache sleep/wake cycle headaches
Key neurological signs Disorientated to time Cognitive impair- Fluctuating atten- Bilateral intention Cognitive impair- Cognitive impairment No focal signs Disorientation;
and place; impaired ment; increased tion and cogni- tremor; heel-shin ment; reduced intermittent agita-
insight; bradyphre- limb tone; brisk tion; bradyphre- ataxia verbal fluency tion; unable to
nia; polyminimyo- reflexes nia; dyspraxia. follow com-
clonus; old left mands; speaking a
homonymous few words only;
hemianopia bilateral extensor
plantars
D-dimer (mg/l; 0–550) 1190 1730 NR 970 NR 2430 1200 NR
Neurological treatments; Supportive; complete Supportive; com- Supportive; Supportive; complete Supportive; Melatonin; on-going Haloperidol, risperi- 1g IVMP 3 days; on-
recovery plete/rehab complete complete cognitive done; improving going
impairment improvement

Imaging, further investigations and Patients 9 and 10 are provided in the Supplementary material. F = female; IVMP = intravenous methylprednisolone; M = male; NR = no result.
R. W. Paterson et al.

Downloaded from https://academic.oup.com/brain/article/143/10/3104/5868408 by guest on 30 July 2021

Table 3 Eight patients with neuroinflammatory diseases (Patients 11–18)

Patient 11 12 13 14 15 16 17 18
Age, M/F, ethnicity, 65, F, Black, definite/ 66, F, White, definite/ 52, M, Asian, def- 60, M, Asian, def- 59, F, Asian, definite/ 52, M, White, defin- 47, F, other, probable/ 54, F, mixed, prob-
COVID-19 diagnosis/ severe mild inite/critical inite/critical mild ite/critical severe able/mild
severity
Final neurological Possible post-infec- Encephalitis ADEM (with ADEM (with ADEM (with necrosis ADEM (with haemor- ADEM (with ADEM
diagnosis tious encephalitis haemorrhage) haemorrhage) and haemorrhage) rhage) and acute haemorrhage)
(presumed demyelinating poly-
autoimmune) radiculoneuropathy
Imaging: neuraxis MRI brain normal MRI brain: T2 hyperin- MRI brain: mul- MRI brain: multi- MRI brain (Day 6): ex- MRI brain: multifocal Severe right hemi- Multiple large
(summary) tense signal changes tiple clusters of focal and con- tensive, confluent confluent lesions in spheric vasogenic lesions with per-
in upper pons, lim- lesions in the fluent areas of and largely symmet- internal and exter- oedema with a ipheral rim re-
bic lobes, medial deep cerebral signal change in rical areas through- nal capsules, sple- leading edge on striction in
The emerging spectrum of COVID-19 neurology

D-dimer if raised; CSF 1800 mg/l (0–550);
studies; all neuronal
antibodies performed
were negative
Treatments for neuro- 1 g IVMP 3 days, oral 1 g IVMP 3 days then
logical diagnosis;
recovery
thalami and subcor- white matter. the cerebral out brainstem, nium and deep contrast imaging. periventricular
tical cerebral white Cyst-like areas hemispheric limbic and insular white matter of Smaller areas of T2 white matter of
matter of varied sizes, white matter lobes, superficial cerebral hemi- hyperintense both cerebral
some with with extensive subcortical white spheres. Over 5 changes in the left hemispheres
haemorrhagic microhaemor- matter and deep days, lesions hemisphere.
foci and periph- rhages in the grey matter. increased in size Marked mass-effect
eral rims of subcortical Clusters of micro- and showed mul- with 10 mm left-
restricted regions haemorrhages, tiple microhaemor- wards midline shift,
diffusion restricted diffusion rhages and and mild subfalcine
and peripheral rim extensive promin- herniation
enhancement ent medullary veins.
Components of
brachial and lumbo-
sacral plexus
showed increased
signal and
enhancement
1599 ng/ml (0–230); 80 000 mg/l (0– 3330 mg/l (250– 2033 mg/l (250–750); NR; CSF protein 1160 mg/l (0–550); NR 19 (90% lymph);
CSF matched OCB, CSF protein raised, 550); OCB 750); CSF OCB CSF OP raised, viral raised, viral PCR CSF NR 0.33; OCB nega-
viral PCR negative OCB, viral PCR negative, viral negative, viral PCR negative negative tive, CSF culture
including SARS- PCR and anti- PCR negative including SARS- scanty
CoV-2 negative bodies negative including SARS- CoV-2 Staphylococcus
CoV-2 capitis (likely
contamination)
Supportive; in- 1 g IVMP 3 days; Intubation, ventilation; Intubation and ventila- Intubation, hemicra- 1 g IVMP 3 days,
prednisolone taper, oral prednisolone complete but incomplete levetiracetam, acic- tion, 1 g IVMP 5 niectomy, 1g IVMP then oral prednis-
levetiracetam, clo- taper, IVIG; ongoing ongoing lovir and ceftriax- days, IVIG; incom- 5 days, oral pred- olone; incomplete
nazepam; incomplete one, dexametha- plete ongoing nisolone, IVIG; in- ongoing recovery
incomplete sone; no response, recovery complete ongoing
died recovery
BRAIN 2020: 143; 3104–3120

Diagnosis, imaging and further investigations for Patients 19–22 are provided in the Supplementary material. F = female; IVMP = intravenous methylprednisolone; M = male; NR = no result; OCB = oligoclonal band; OP = opening pressure.
| 3109

Downloaded from https://academic.oup.com/brain/article/143/10/3104/5868408 by guest on 30 July 2021

 3110

Table 4 Eight patients with stroke (Patient 23–30)

Patient 23 24 25 26 27 28 29 30
Age, M/F, ethnicity, 61, M, Black, definite/ 64, M, White, defin- 64, M, White definite/ 53, F, Asian, definite/ 58, M, Black, prob- 85, M, White, defin- 73, M, Asian, definite/ 27, F, White,
COVID-19 diagnosis, mild, 2 days ite/severe , 15 days severe, NK severe, 22 days able/mild, 2 days ite/mild, 10 days mild, 8 days probable/
severity, time from mild, 0 days
COVID onset
Stroke type, observed/ Ischaemic right middle Ischaemic, vertebral- Ischaemic bilateral Ischaemic, vertebral- Ischaemic, proximal Ischaemic, left poster- Ischaemic basilar ar- Ischaemic left in-
| BRAIN 2020: 143; 3104–3120

implicated mechan- cerebral artery oc- basilar artery occlu- ACA-MCA and basilar artery occlu- left middle cerebral ior cerebral artery tery occlusion, no ternal cere-
ism; venous clusion; yes, PE sion; yes, PE MCA-PCA cortical sion; no artery occlusion; occlusion; no bral artery
thromboembolism and deep border- yes PE occlusion; yes
zone infarct; no PE
Fibrinogen (g/l; 1.5–4.0), 4.63, 27 190, 10.7 9.5, 80 000, 11.6 8.82, 29 000, 12.6 2.91, 7750, 34.4 3.15, 75 320, 12,2 5.3, 16 100, 11.3 NR, NR, 14.9 NR, NR, 11.5
D-dimer (mg/l; 0–
550), Prothrombin
time (s; 10–12)
Brain imaging MRI: acute infarct in MRI: (1st event): MRI: subacute infarcts Non-contrast CT: MRI: extensive evolv- Non-contrast CT: MRI: acute infarction CT: right middle
(summary) the right corpus acute left vertebral within the deep in- showed acute right ing left MCA infarct showed hyperden- in the right thal- cerebral ar-
striatum. Multiple artery thrombus ternal border zones parietal cortical and with evidence of sity consistent with amus, left pons, tery and right
supra- and infra- and acute left pos- of the cerebral left cerebellar in- petechial haemor- thrombus in the left right occipital lobe anterior cere-
tentorial cortical terior-inferior cere- hemispheres bilat- farct with mass ef- rhage and associ- posterior cerebral and right cerebellar bral artery
and subcortical bellar artery erally, and within fect and ated mass-effect as artery and acute in- hemisphere territory
micro- territory infarction the left frontal hydrocephalus, des- described. farction in the left infarction
haemorrhages with microhaemor- white matter. pite therapeutic Persistent occlusion temporal stem and
rhages. 2nd event, 7 Background moder- anticoagulation of the left M2 MCA cerebral peduncle
days later: bilateral ate small vessel dis- branches
acute posterior ease and
cerebral artery ter- established cortical
ritory infarcts des- infarcts, in arterial
pite therapeutic border zone
anticoagulation territories
Tissue plasminogen acti- No, no, LMWH No, no, LMWH No, no, LMWH No, no, LMWH No, no, LMWH No, no, aspirin 7 days Yes, no, aspirin 5 days Aspirin 10 days
vator, mechanical then switched to then switched to then LMWH
ventilation, anti- apixaban LMWH
thrombotic therapy
Outcome status Rehabilitation unit Rehabilitation unit Remains static in ICU Died Rehabilitation unit Rehabilitation unit Stroke unit Rehabilitation
(Day 31) unit

ACA = anterior cerebral artery F = female; ICU = intensive care unit; LMWH = low molecular weight heparin; M = male; MCA = medial cerebral artery; NK = not known; NR = no result; PCA = posterior cerebral artery; PE = pulmonary
embolism.
R. W. Paterson et al.

Downloaded from https://academic.oup.com/brain/article/143/10/3104/5868408 by guest on 30 July 2021

The emerging spectrum of COVID-19 neurology
course fluctuated over 3 weeks with a trend towards im-
provement, albeit after the introduction of haloperidol, fol-
lowed by risperidone.
Neuroinflammatory syndromes
Twelve patients (Patients 11–22, 27–66 years old; eight fe-
male, four male; four White, three Black, three Asian; two
other/mixed) presented with inflammatory CNS syndromes.
Two had an encephalitis; one (Patient 11, Vignette B) had
features of an autoimmune encephalitis with opsoclonus,
stimulus sensitive myoclonus and convergence spasm.
Although brain imaging, EEG and CSF were normal, the
clinical picture was highly suggestive of an autoimmune
brainstem encephalitis. The second encephalitis patient
(Patient 12) presented with confusion and a single seizure,
with MRI abnormalities suggestive of autoimmune or ‘lim-
bic’ encephalitis in the thalami, medial temporal regions and
pons (Fig. 1A–D, Table 3 and Supplementary material).
Nine patients were categorized within the spectrum of
ADEM (e.g. Vignette C, Fig. 1E–H). Four patients had
haemorrhagic change on imaging, including microbleeds;
and one had necrosis. Two patients had myelitis in addition
to brain imaging changes, and one further had myelitis with
normal brain imaging. Patient 17 (Vignette D) with acute
haemorrhagic leucoencephalitis (based on clinical and imag-
ing features) failed to respond to corticosteroids and
required decompressive craniectomy for incipient brain her-
niation; a brain biopsy at the time of surgery showed evi-
dence of perivenular inflammation supporting aggressive
hyper-acute ADEM. She made significant recovery after the
decompression followed by intravenous immunoglobulin
(IVIG), but requires ongoing rehabilitation. Patient 15 devel-
oped a severe necrotizing encephalitis (Fig. 1I–P) that
resulted in death. Patient 16 was unusual in presenting with
a GBS and subsequently developed an ADEM-like illness
(Fig. 2H–O, Vignette E).
Despite the striking imaging findings of these patients
(Figs 1–3), the CSF parameters were abnormal in only half.
In none of the cases tested were specific antibodies (e.g. to
NMDAR, MOG, AQP4, LGI1 or GAD) identified in the
serum or CSF. Treatments were with corticosteroids in nine,
and IVIG in three. A full clinical response was seen in 1 of
12, partial recovery at the time of writing in 10 of 12, and
one patient died.
Vignette B: post-infectious probable brainstem and
cortical autoimmune encephalitis
A 65-year-old female (Patient 11), with a 2-year history of
cognitive decline and presumed sporadic early onset
Alzheimer’s disease, presented with right hand and then
widespread involuntary movements, 6 days after fever,
cough and myalgia. She had difficulty speaking and became
disorientated and confused, complaining of well-formed vis-
ual hallucinations of people inside her house and objects fly-
ing around the room. She complained of deteriorating
vision, with difficulty reading, and intermittent double
BRAIN 2020: 143; 3104–3120 | 3111
vision. On admission she had widespread stimulus sensitive
myoclonus involving the tongue and all four limbs with
marked hyperekplexia. There was episodic opsoclonus and
prominent convergence spasm on visual fixation. She had a
non-fluent aphasia with oral apraxia, difficulty repeating
sentences and was only able to follow single stage com-
mands. MRI brain, EEG and CSF examination were normal.
SARS-CoV-2 PCR was positive on nasopharyngeal swab.
Levetiracetam and clonazepam were used to treat her myo-
clonus, and 2 weeks after onset of neurological symptoms,
she received a course of steroids for a clinical diagnosis of
presumed post-infectious autoimmune encephalitis affecting
cortex and brainstem. Cognition and visual symptoms
Downloaded from https://academic.oup.com/brain/article/143/10/3104/5868408 by guest on 30 July 2021
improved although there are on-going symptoms at the time
of writing.
Vignette C: ADEM with haemorrhage in a critically
ill patient
A 52-year-old male (Patient 13) presented with a 10-day his-
tory of cough, fever, dyspnoea and myalgia. On admission
he was hypoxic and non-invasive ventilation was com-
menced. He had bilateral chest X-ray changes consistent
with COVID-19 and SARS-CoV-2 RNA PCR was positive.
Oxygen requirements increased and mechanical intubation
was required. On Day 17 of intensive care admission he was
slow to wean from sedation. His conscious level was
impaired (responding to pain only) despite a prolonged with-
drawal from sedation. He was hyper-reflexic with lower
limb clonus. Brain MRI showed bilateral white matter
changes with haemorrhage (Fig. 1E–H). There was slow and
still on-going neurological improvement over 4 weeks with
supportive treatment alone, which continues at the time of
writing.
Vignette D: acute haemorrhagic
leukoencephalopathy form of ADEM requiring
decompressive craniectomy
A 47-year-old female (Patient 17), previously well and who
worked in a high-risk occupation for COVID-19, presented
with right-sided headache and left hand numbness. This was
preceded by 7 days of cough, fever and shortness of breath.
On the day of presentation, she had persistent severe head-
ache and progressive onset of left-sided numbness followed
by left-sided weakness including the face. A few hours later,
she was drowsy, with severe left upper limb weakness, mild
left leg weakness and hemisensory loss. CT head imaging
demonstrated marked right hemisphere vasogenic oedema
with midline shift. She required 4 l of oxygen and had lower
zone chest X-ray and CT chest changes compatible with
probable COVID-19 as well as lymphopenia, and elevated
D-dimer. Head MRI demonstrated severe right hemispheric
vasogenic oedema with a leading edge on contrast imaging,
and smaller areas of T2 hyperintense changes in the left
hemisphere, in keeping with a diagnosis of an acute haemor-
rhagic leukoencephalopathy form of ADEM. She was
treated with high dose intravenous methylprednisolone (1 g
daily for 5 days). After 48 h of treatment her conscious level
3112 | BRAIN 2020: 143; 3104–3120 R. W. Paterson et al.

Downloaded from https://academic.oup.com/brain/article/143/10/3104/5868408 by guest on 30 July 2021

Figure 1 Imaging from Patients 12, 13 and 15 (COVID-19 autoimmune and haemorrhagic encephalitis). Axial MRI from three
individuals with para-/post-infectious central syndromes. (A–D) Patient 12: axial fluid-attenuated inversion recovery (FLAIR) images show bilat-
eral hyperintensity in the mesial temporal lobes (A and B), hypothalamus (C) temporal lobes and thalamus (D). (E–H) Patient 13: axial T2-
weighted (E), diffusion weighted imaging (DWI) (F), susceptibility weighted imaging (SWI) (G) and post-contrast T1-weighted (H) images show
multifocal clusters of lesions involving the deep white matter of both cerebral hemispheres, intralesional cyst-like areas of varied sizes, and some
peripheral rims of restricted diffusion (F), some haemorrhagic changes (G), and T1 hypointense ‘black holes’ without contrast enhancement (H).
(I–P) Patient 15: axial images at the level of the insula and basal ganglia (I–L) and at the level of the temporal lobes and upper pons (M–P). T2-
weighted images (I and M), SWI images (J and N), DWI images (K and O) and contrast-enhanced images (L and P). There are extensive conflu-
ent areas of T2 hyperintensity (I and M), with haemorrhagic change on SWI imaging (J and N), restricted diffusion on DWI images (K and O) and
peripheral contrast-enhancement (arrows in L and P) in the insular region, basal ganglia and left occipital lobe (I–L) as well as in the medial tem-
poral lobes and upper pons (M–P).
The emerging spectrum of COVID-19 neurology BRAIN 2020: 143; 3104–3120 | 3113

Downloaded from https://academic.oup.com/brain/article/143/10/3104/5868408 by guest on 30 July 2021

Figure 2 Axial MRI (A–D) and histopathology (E–G) from Patient 17, diagnosed with ADEM, and imaging (H–O) from Patient
16, with combined CNS and PNS disease. (A–G) Patient 17: axial T2-weighted (A), SWI (B), post-gadolinium (C and D) images show ex-
tensive confluent ‘tumefactive’ lesions involving the white matter of the right cerebral hemisphere, corpus callosum and corona radiata with mass
effect, subfalcine herniation (A), clusters of prominent medullary veins (B, short arrows) and peripheral rim enhancement (D, arrows). (E) The
white matter shows scattered small vessels with surrounding infiltrates of neutrophils and occasional foamy macrophages extending into the par-
enchyma (arrow). The endothelium is focally vacuolated but there is no evidence of vasculitis or fibrinoid vessel wall necrosis in any region.
There were a few perivascular T cells in the white matter but the cortex appears normal (not shown). (F) CD68 stain confirms foci of foamy
macrophages in the white matter, mainly surrounding small vessels. There was no significant microgliosis in the cortex (not shown). (G) Myelin
basic protein stain (SMI94) shows areas with focal myelin debris in macrophages around vessels in the white matter (arrows) in keeping with early
myelin breakdown. There is no evidence of axonal damage on neurofilament stain (not shown). Scale bars: E = 45 mm; F and G = 70 mm. (H–O)
Patient 16: axial post-gadolinium fat-suppressed T1-weighted images (H) demonstrating pathologically enhancing extradural lumbosacral nerve
roots (arrows). Note physiological enhancement of nerve root ganglia (short arrows). Coronal short tau inversion recovery (STIR) image (L)

(continued)
3114 | BRAIN 2020: 143; 3104–3120
fell, she developed a fixed dilated right pupil and underwent
emergency right hemi-craniectomy. She subsequently
received oral prednisolone 60 mg daily and 5 days of IVIG.
She was extubated 4 days postoperatively and continues to
improve clinically, and is able to weight bear with support.
Pathological findings from brain biopsy taken at surgery
supported a diagnosis of hyperacute ADEM (Fig. 2E–G).
The brain tissue was negative in PCR for SARS-CoV-2.
Vignette E: sequential para-infectious involvement
of central and peripheral nervous systems
A 52-year-old male (Patient 16) presented with a 3-day his-
tory of headache, back pain, vomiting and progressive limb
weakness. There was bilateral facial and neck weakness,
symmetrical upper and lower limb flaccid (proximal 4 dis-
tal) weakness, generalized areflexia, extensor plantar
responses and preserved sensation. MRI of the neuroaxis
was normal except for gadolinium enhancement of the cer-
vical and lumbar roots (Fig. 2H and L). CSF was acellular,
with a raised protein. Nerve conduction studies supported a
diagnosis of GBS and he was treated with IVIG. On Day 3
of admission, he deteriorated with increasing weakness, dys-
phagia, ophthalmoplegia, and lymphopenia. Due to type-2
respiratory failure, he required ventilation. The patient be-
came febrile (38.9 C), with increasing oxygen requirements,
and antibiotics were commenced. Chest CT showed bilateral
pulmonary infiltrates. SARS-CoV-2 RNA PCR was positive
on throat swab, but negative in CSF. On Day 5, he became
unresponsive and a repeat brain MRI showed a pattern of
T2 symmetrical widespread white matter hyperintensities,
which progressed further on Day 12 (Fig. 2I–K and M–O).
Intravenous methylprednisolone (IVMP, 1 g/day) was given
for 5 days, with neurological improvement following treat-
ment on Day 3: eyes opened spontaneously, he could obey
commands, mouth words, and move both hands. Two weeks
after completion of IVMP the patient was alert, breathing
without assistance, talking and able to flex both arms.
Stroke
Eight patients (Patients 23–30; aged 27–64, six male, two fe-
male, four White, two Black, two Asian) had ischaemic
stroke in the context of hypercoagulability and a significant-
ly raised D-dimer (47000 mg/l) in each of the six cases
measured. Thrombus was observed in large intra- and extra-
cranial vessels in four patients. Four patients had pulmonary
thromboembolism (e.g. Patient 27, Vignette F) (Table 4).
Figure 2 Continued
shows hyperintense signal abnormality of the upper trunk of the right brachial plexus (arrow). Initial axial T2 (I and J) and T2*-weighted images
(K) show multifocal confluent T2 hyperintense lesions involving internal and external capsules, splenium of corpus callosum (I), and the juxtacort-
ical and deep white matter (J), associated with microhaemorrhages (K, arrows). Follow-up T2-weighted images (M and N) show marked progres-
sion of the confluent T2 hyperintense lesions, which involve a large proportion of the juxtacortical and deep white matter, corpus callosum and
internal and external capsules. The follow-up SWI image (O) demonstrates not only the previously seen microhaemorrhages (arrows) but also
prominent medullary veins (short arrows).
R. W. Paterson et al.
Vignette F: ischaemic stroke with concurrent
pulmonary embolism
A 58-year-old male (Patient 27), previously independent in a
high-risk occupation for developing COVID-19, presented
with acute onset aphasia and dense right-sided weakness.
This was preceded by a 2-day history of lethargy and cough.
He was found to be drowsy and unresponsive. Brain CT con-
firmed a proximal middle cerebral artery thrombus and terri-
torial infarct (Fig. 4A–D) with local mass effect. He was
transferred to a specialist hospital due to risk of vasogenic oe-
dema leading to malignant middle cerebral artery syndrome.
Due to the degree of established infarction neither intraven-
ous thrombolysis nor mechanical thrombectomy were appro-
Downloaded from https://academic.oup.com/brain/article/143/10/3104/5868408 by guest on 30 July 2021
priate. CT angiogram also showed a saddle pulmonary
embolism, which was managed conservatively with split dose
low molecular weight heparin. His condition was critical in
the hyperacute period with fluctuating level of consciousness
and tachycardia, but stabilized. His D-dimer was in excess of
80 000 mg/l on admission but reduced to 2800 mg/l after 7
days of anticoagulation. Lupus anticoagulant was positive.
The patient was discharged to a rehabilitation unit on Day 8.
Peripheral nervous system
Seven patients (Patients 31–38) with GBS were seen (aged
20–63, all male, five White, one Black, one other), with
onset of neurological symptoms from 1 day before to 21
days after typical COVID-19 symptoms. One patient devel-
oped a brachial plexopathy onset 2 weeks after COVID-19
symptoms. Of this group, half had definite COVID-19, three
requiring intensive care. All GBS patients were treated with
IVIG; the patient with brachial plexopathy received cortico-
steroids. All but two of this group have started to make par-
tial recovery at the time of writing.
Miscellaneous
The remaining five patients (Patients 39–43) were difficult to
categorize. They comprised myelopathy with normal imag-
ing; one patient with bilateral abducens nerve palsy due to
intracranial hypertension (pseudo-tumour cerebri) who pre-
sented with abdominal pain, diarrhoea and rash and had
possible cardiac involvement with COVID-19; a complex
paediatric case with a congenital developmental disorder
and stable epilepsy who developed non-convulsive status epi-
lepticus; and a patient with a bacterial brain abscess with
Streptococcus intermedius. One patient, a 27-year-old male
with acute myeloid leukaemia, COVID-19 lung disease and
The emerging spectrum of COVID-19 neurology BRAIN 2020: 143; 3104–3120 | 3115

Downloaded from https://academic.oup.com/brain/article/143/10/3104/5868408 by guest on 30 July 2021

Figure 3 Patients 19 and 20 (ADEM including spinal cord). Patient 19: axial T2 (A and C) and DWI (B and D) images show multifocal
lesions involving corpus callosum and corona radiata. Patient 20: axial T2-weighted images of brain MRI and sagittal T2-weighted of the spinal
cord acquired on admission (E–H) and after 26 days (I–L). Axial T2-weighted images show multifocal hyperintense lesions in the brainstem (E
and I), basal ganglia and supratentorial white matter (F and J). The pontomedullary hyperintensities have become more confluent (I) since admis-
sion (E). After 26 days, the signal abnormalities in the basal ganglia and the supratentorial white matter (J) are grossly similar to the baseline MRI
scan (F). Sagittal and axial T2-weighted images show diffuse high T2-weighted signal intrinsic to the spinal cord at baseline (G and H). After 26
days, the cord oedema has reduced, and the spinal cord lesions appear less confluent and more discrete (K and L).

seizures with some encephalopathy, demonstrated a signifi-
cant burden of microhaemorrhages (Patient 41; Fig. 4E–H).
He had been treated with gilteritinib as part of his acute
myeloid leukaemia therapy.
Summary of key features
Despite the wide range of initial presentations, with a better
appreciation of the five main categories outlined above, the
key clinical features and investigations could be proposed as
summarized in Table 1. None of the eight patients tested for
SARS-CoV-2 PCR in CSF were positive, and none of the
autoantibodies seen in autoimmune forms of encephalitis
(NMDAR, LGI1) or encephalomyelitis (AQP4, MOG) were
detected in serum or CSF samples. Raised D-dimers were,
predictably, highly raised in those patients with stroke but
were also above normal levels, and occasionally markedly
elevated in each of the other groups. Those with encephalo-
pathies improved without specific treatments. The patients
with inflammatory CNS diseases were treated with cortico-
steroids (n = 10) and corticosteroids in combination with
IVIG (n = 3) and have had variable outcomes to date, but
the follow-up period is still short. One patient with ADEM
made some improvement spontaneously without specific
3116 | BRAIN 2020: 143; 3104–3120 R. W. Paterson et al.

Downloaded from https://academic.oup.com/brain/article/143/10/3104/5868408 by guest on 30 July 2021

Figure 4 Imaging from Patient 27, with cerebral infarction and pulmonary thromboembolism (A–D), and Patient 41, with
microhaemorrhages (E–H). (A–D) Patient 27: CT pulmonary angiogram (A) demonstrated large emboli in the right and left pulmonary
arteries (arrows). DWI (B), T2-weighted FSE (C) and SWI (D) images show restricted diffusion (B) and T2 hyperintensity (C) in the left basal
ganglia and cortical territory of left middle cerebral artery. The SWI image (D) shows haemorrhagic transformation in the basal ganglia (short
arrow) and a long intravascular thrombus in a Sylvain branch of the left middle cerebral artery (long arrow). (E–H) Patient 41: chest CT (E)
shows severe COVID-19 pneumonitis. SWI images (F–H) demonstrate numerous cerebral microbleeds in the temporal, frontal and parietal
lobes, predominantly located at the grey/white matter junction.

treatment. Six of seven patients with GBS had partial re-
sponse to treatment at the time of writing.
Discussion
The widespread effects of COVID-19 include neurological
disorders but there have been, to date, no detailed clinical
reports of their nature (Guan et al., 2020; Helms et al.,
2020; Mao et al., 2020; Varatharaj et al., 2020). Our
London and regional cohort describes a range of neurologic-
al syndromes including encephalopathies, para- and post-
infectious CNS syndromes including encephalitis, ADEM
with haemorrhage and necrotic change, transverse myelitis,
ischaemic stroke and GBS.
The neurological complications of SARS-CoV2 have simi-
larities to those described in the other coronavirus epidemics,
specifically severe acute respiratory syndrome (SARS) in
2003, and Middle East acute respiratory syndrome (MERS)
in 2012. The cases described in those reports included en-
cephalopathy, encephalitis and both ischaemic and haemor-
rhagic stroke attributed to hypercoagulability, sepsis and
vasculitis, and GBS (Umapathi et al., 2004; Tsai et al., 2005;
Kim et al., 2017). However, overall numbers of infected
individuals were much smaller, 8000 with SARS and 2500
with MERS, and neurological presentations were therefore
few in comparison with those being recognized in the cur-
rent pandemic.
In a series from Wuhan, 78 of 214 COVID-19 patients,
recruited over 4 weeks, developed neurological manifesta-
tions. These patients tended to be more severely affected,
older and with more comorbidities and, for some, the
neurological symptom was the first presentation of
COVID-19 (Mao et al., 2020). However, apart from
stroke in six patients (2.8%), the neurological features
could be due to viral infection (loss of smell and taste) or
to the consequences of severe systemic illness in an inten-
sive care setting, such as sepsis and hypoxia. More specific
details came from 64 consecutive patients reported by the
Strasbourg group (Helms et al., 2020) with agitation in
40/58 (69%), confusion in 26/40 (65%) and corticospinal
tract signs in 39/59 (67%). MRI abnormalities were seen
in 22 patients with meningeal enhancement, ischaemic
stroke and perfusion changes. CSF examination was nega-
tive for SARS-CoV-2 in all seven cases tested. There are
isolated case reports in the literature of myoclonus
(Rábano-Suárez et al., 2020) and demyelination
(Varatharaj et al., 2020; Zanin et al., 2020).
The emerging spectrum of COVID-19 neurology
Ten of our patients had transient encephalopathies with
features of delirium, and psychosis in one. Delirium with
agitation is described in case reports and in the larger studies
mentioned above, and cognitive dysexecutive syndromes
have been reported at discharge (Rogers et al., 2020). While
our patients had transient syndromes, detailed neuropsycho-
logical testing and follow-up is required to determine the ex-
tent of cognitive dysfunction in recovery, and to examine
psychiatric and psychological factors (Brown et al., 2020).
The underlying mechanisms for the encephalopathy may be
multifactorial resulting from the combined or independent
effects of sepsis, hypoxia and immune hyperstimultion
(‘cytokine storm’) (Mehta et al., 2020).
Two of our cases had a probable autoimmune encephal-
itis, one with typical clinical features of opsoclonus and
myoclonus, and another with typical radiological images as
seen in ‘limbic’ encephalitis (Graus et al., 2016). These
patients did not have NMDAR, LGI1 or related autoanti-
bodies (Supplementary Table 1). The issue of whether
SARS-CoV-2 will trigger a significant number of cases of
autoimmune encephalitis, with probable antibody-mediated
mechanisms, will become clear in time.
The cluster of cases with an ADEM-like illness warrants
close surveillance. ADEM, an immune-mediated demyelinat-
ing disorder, is a disease mainly of children (Pohl et al.,
2016), with an adult incidence in the UK of 0.23/100 000
(Granerod et al., 2010; Absoud et al., 2015). The nine cases
described were accrued over a 5-week period. In Greater
London (population 9 million, Office for National Statistics,
2019), we would expect to see this incidence of cases in 5
months, which indicates that COVID-19 is associated with
an increased incidence of ADEM. SARS-CoV-2 was not
detected in CSF in any of the eight patients tested and the
single neuropathological sample obtained did not confirm
the presence of SARS-CoV-2 in brain tissue, and was sup-
portive of the diagnosis of ADEM. While we cannot exclude
the possibility of direct CNS infection in some cases, without
further neuropathological studies or development of accurate
CSF viral markers and serological testing, the imaging and
clinical features are most supportive of a para- or post-infec-
tious disease mechanism. Long-term follow-up is now
required to establish the natural history of the cases that we
have identified.
The GBS cases were not unexpected. The temporal rela-
tionship between the COVID-19 respiratory illness and the
onset of symptoms would be consistent with a post-infec-
tious immune-mediated mechanism. Up to two-thirds of
patients with GBS describe an antecedent respiratory or
gastroenterological illness. The most common pathogens in-
clude Campylobacter jejuni, cytomegalovirus, Mycoplasma
pneumonia, HIV and more recently the Zika virus. The first
report of GBS and SARS-CoV-2 from Italy describes five
cases of GBS out of a total of 1200 admissions (Toscano
et al., 2020). The expected incidence of GBS is 0.6–2.7/
100 000/year (Willison et al., 2016) and further epidemio-
logical and mechanistic study is required to determine if
there is a true increase in incidence of GBS in COVID-19
BRAIN 2020: 143; 3104–3120 | 3117
patients. Our GBS cases appeared to be similar to conven-
tional GBS patients with respect to clinical presentation,
neurophysiology showing demyelinating changes in the ma-
jority of patients, CSF parameters and the response to treat-
ment with IVIG.
Stroke associated with a generalized thrombotic predispos-
ition in COVID-19 is of particular interest. Four out of the
eight patients had cardiovascular risk factors for stroke
including atrial fibrillation. Four also had pulmonary
emboli. COVID-19 is associated with a pro-thrombotic state
and highly elevated D-dimer levels, and abnormal coagula-
tion parameters have been shown to be associated with poor
outcome (Tang et al., 2020). The frequent occurrence of
Downloaded from https://academic.oup.com/brain/article/143/10/3104/5868408 by guest on 30 July 2021
cerebral microbleeds seen in some of the patients, however,
was unexpected (Fig. 4). Cerebral microbleeds are usually
due to extravasation of red blood cells, and in the context of
COVID-19 could be due to endothelial dysfunction related
to viral binding to the ACE-2 receptors expressed on endo-
thelial cells. Indeed, a recent report described direct viral in-
fection of the endothelial cell and diffuse endothelial
inflammation in multiple organ systems (Varga et al., 2020).
The strokes we have encountered with COVID-19 have
been severe, and further epidemiological study is required to
determine the association between COVID-19 and stroke;
randomized trials to determine the optimal use of antiplate-
let drugs, low molecular weight heparin and other stroke
therapies are required.
Muscle pain and elevated creatinine kinase have been
reported as relatively common manifestations of SARS-
CoV-2 infection (Chen et al., 2020; Guan et al., 2020;
Huang et al., 2020) and there are case reports of rhabdo-
myolysis (Rivas-Garcia et al., 2020). Like other large
neurological case series (Varatharaj et al., 2020), we did
not observe such cases, but this could reflect referral bias
to our MDT, which was set up to discuss the most chal-
lenging and severe cases.
Within our cohort of 12 patients with CNS inflammatory
syndromes, a range of clinical and radiological presentations
were observed, including some suggestive of post-infective
ADEM or transverse myelitis and others with more unusual
haemorrhagic changes that made classification challenging.
A recent MRI study of 37 patients with severe COVID-19
and abnormal brain imaging found three patterns of CNS
white matter changes, which could occur in isolation or in
combination (Kremer et al., 2020). Pattern 1 featured medial
temporal lobe signal abnormalities similar to that seen in
viral or autoimmune encephalitis; whereas patterns 2 and 3
featured microhaemorrhages, either in the context of multi-
focal white matter hyperintense lesions or as separate fea-
tures, respectively. Whether these patterns represent the
same pathology over different timelines, different immuno-
logical or other mechanisms, or combinations, is currently
unclear, but could have important implications for manage-
ment decisions, such as the use of steroids, and rehabilita-
tion. In the Kremer et al. (2020) study, haemorrhagic lesions
correlated with clinical indicators of disease severity.
Especially in the intensive care cohort, it can be unclear
3118 | BRAIN 2020: 143; 3104–3120
when brain injury occurs, as imaging is usually only under-
taken when a patient is slow to wake after a prolonged
period of ventilation.
Histopathological correlates are now emerging for some
lesions. Reichard et al. (2020) described a case similar to
those described in the Kremer et al. (2020) study and
reported features of both vascular and ADEM-like path-
ology, with macrophages and axonal injury. Conversely,
von Weyhern et al. (2020) found lymphocytic panencephali-
tis and meningitis, and brainstem perivascular and interstitial
inflammatory change with neuronal loss as prominent fea-
tures in six post-mortem patients. In our one case who
underwent cranial decompression, brain histology was in
keeping with ADEM. Similar to the ADEM-like cases, the
GBS cases also largely point to a post-infectious autoimmune
mechanism, with most developing the neurological disease
within 3 weeks of the documented infection. The risk factors
for neurological disease remain unknown, and require fur-
ther epidemiological study.
The potential mechanisms underpinning the syndromes
described include either individually, or in combination, dir-
ect viral injury, a secondary hyperinflammation syndrome
related to cytokines including IL-6 (Mehta et al., 2020), vas-
culopathy and/or coagulopathy, post-infectious inflamma-
tion including autoantibody production to neuronal
antigens, and the effects of a severe systemic disorder with
the neurological consequences of sepsis and hypoxia.
Evidence of direct viral infection has proved elusive so far
with only a few cases with SARS-CoV-2 in CSF reported,
and few supportive histopathological features, though clearly
further study would be helpful (Reichard et al., 2020, von
Weyhern et al., 2020). Elevation of pro-inflammatory cyto-
kines was found to correlate with COVID-19 disease sever-
ity (Herold et al., 2020; Huang et al., 2020), and some
patients responded to IL-1 or IL-6 blockade (Cavalli et al.,
2020; Price et al., 2020); in support of this possible mechan-
ism, transient splenial lesions have been reported in a num-
ber of cases, including in children with multisystem
inflammatory syndrome (MIS-C), in which elevated cyto-
kines are thought to play a role (Starkey et al., 2017; Abdel-
Mannan et al., 2020; Hayashi et al., 2020; Riollano-Cruz et
al., 2020). Interestingly, some of the clinical features seen in
our youngest patient (Patient 39, aged 16 with pseudotu-
mour cerebri with cranial nerve palsies) overlapped with
those seen in MIS-C, including gastrointestinal symptoms,
rash and cardiac involvement (Supplementary Table 1).
Exact mechanisms in each case will be largely speculative
until clear clinical, radiological and histological correlates
have been drawn; given the breadth of clinical presentations,
it is likely that a number or spectrum of these mechanisms
are involved.
Collectively, these cases presented a considerable chal-
lenge to diagnose with MRI, neurophysiology including
EEG, being difficult to obtain in an intensive care setting
in addition to the demands of safe nursing and infection
control. In many cases, MRI proved essential for making
the diagnosis or confident exclusion of abnormalities,
R. W. Paterson et al.
especially in patients in the intensive care unit who were
‘slow to wake’. In addition, controversy remains regarding
the optimal treatment options including the use of high
dose corticosteroids in viraemic, and often lymphopenic
patients, and the potential risks of using IVIG for ADEM
and GBS, in patients with pro-thrombotic risk factors
such as elevated D-dimer levels.
This is a selective and retrospective study, with the limita-
tions associated with this study design, including bias to-
wards severe disease. Nevertheless, the study has allowed a
detailed description of the neurological complications seen
during and after COVID-19 infection. Further detailed clin-
ical, laboratory, biomarker and neuropathological studies
Downloaded from https://academic.oup.com/brain/article/143/10/3104/5868408 by guest on 30 July 2021
will help elucidate the underlying pathobiological mecha-
nisms of COVID-19 neurological complications.
Longitudinal follow-up studies of patients will be necessary
to ascertain the long-term neurological consequences of this
pandemic.
Acknowledgements
We acknowledge the patients and their families and friends,
and the referring clinicians.
Funding
R.W.P. is supported by an Alzheimer’s Association Clinician
Scientist Fellowship and by the UK Dementia Research
Institute. R.L.B. is supported by a Medical Research Council
Clinical Research Training Fellowship (555106). S.W. is sup-
ported by the Ministry of Science, Research and the Arts of
Baden-Württemberg and the European Social Fund of
Baden-Württemberg (31-7635 41/67/1). S.K. is a clinical re-
search fellow funded by the Guarantors of Brain and
Association of British Neurologists. D.A. is supported by a
European Research Council Advanced Investigator Award
(BrainEnergy, 740427) and a Wellcome Trust Senior
Investigator Award (219366/Z/19/Z). J.S. is supported by
the NIHR Maudsley Biomedical Research Centre. D.J.W.,
R.J.P., and R.S. have received support for the Stroke
Investigation in North and Central London (SIGNAL) pro-
ject from the NIHR UCL/UCLH Biomedical Research
Centre. R.W.P., R.N., R.S., S.A.T., J.M.M., M.P.L., and
M.S.Z. are supported by the NIHR UCL/UCLH Biomedical
Research Centre.
Competing interests
C.C. has sat on an advisory panel for Roche. A.V. and the
University of Oxford hold patients and receive royalties for
antibody tests. M.S.Z. has received lecturing fees for Eisai
and UCB pharma. All other authors report no competing
interests.
The emerging spectrum of COVID-19 neurology
Supplementary material
Supplementary material is available at Brain online.
References
Abdel-Mannan O, Eyre M, Löbel U, Bamford A, Eltze C, Hameed B,
et al. Neurologic and radiographic findings associated with COVID-
19 infection in children: a case series. JAMA Neurol 2020; doi:
10.1001/jamaneurol.2020.2687.
Absoud M, Lim MJ, Appleton R, Jacob A, Kitley J, Leite MI, et al.
Paediatric neuromyelitis optica: clinical, MRI of the brain and prog-
nostic features. J Neurol Neurosurg Psychiatry 2015; 86: 470–2.
Beyrouti R, Adams ME, Benjamin L, Cohen H, Farmer SF, Goh YY,
et al. Characteristics of ischaemic stroke associated with COVID-19.
J Neurol Neurosurg Psychiatry 2020; jnnp-2020-323586.
Brown E, Gray R, Lo Monaco S, O’Donoghue B, Nelson B,
Thompson A, et al. The potential impact of COVID-19 on psych-
osis: a rapid review of contemporary epidemic and pandemic re-
search. Schizophrenia Res 2020; S0920-9964(20)30257-7.
Cavalli G, De Luca G, Campochiaro C, Della-Torre E, Ripa M,
Canetti D, et al. Interleukin-1 blockade with high-dose anakinra in
patients with COVID-19, acute respiratory distress syndrome, and
hyperinflammation: a retrospective cohort study. Lancet Rheumatol
2020; 2: e325–31.
Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al.
Epidemiological and clinical characteristics of 99 cases of 2019
novel coronavirus pneumonia in Wuhan, China: a descriptive study.
The Lancet 2020; 395: 507–13.
Dixon L, Varley J, Gontsarova A, Mallon D, Tona F, Muir D, et al.
COVID-19-related acute necrotizing encephalopathy with brain
stem involvement in a patient with aplastic anemia. Neurol
Neuroimmunol Neuroinflamm 2020; 7: e789
Ellul MA, Benjamin L, Singh B, Lant S, Michael BD, Easton A, et al.
Neurological associations of COVID-19. Lancet Neurol 2020; doi:
10.1016/S1474-4422(20)30221-0.
Franceschi AM, Ahmed O, Giliberto L, Castillo M. Hemorrhagic pos-
terior reversible encephalopathy syndrome as a manifestation of
COVID-19 infection. Am J Neuroradiol 2020; 41: 1173–6.
Granerod J, Ambrose HE, Davies NW, Clewley JP, Walsh AL,
Morgan D, et al. Causes of encephalitis and differences in their clin-
ical presentations in England: a multicentre, population-based pro-
spective study. Lancet Infect Dis 2010; 10: 835–44.
Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, et al. A
clinical approach to diagnosis of autoimmune encephalitis. Lancet
Neurol 2016; 15: 391–404.
Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical characteris-
tics of coronavirus disease 2019 in China. N Engl J Med 2020; 382:
1708–20.
Hayashi M, Sahashi Y, Baba Y, Okura H, Shimohata T. COVID-19-
associated mild encephalitis/encephalopathy with a reversible sple-
nial lesion. J. Neurol. Sci 2020; 415: 116941.
Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, Kummerlen
C, et al. Neurologic features in severe SARS-CoV-2 infection. N
Engl J Med 2020; 382: 2268–70.
Herold T, et al. Elevated levels of IL-6 and CRP predict the need for
mechanical ventilation in COVID-19. J. Allergy Clin Immunol 2020;
146: 128–36.e4.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features
of patients infected with 2019 novel coronavirus in Wuhan. China.
Lancet 2020; 395: 497–506.
Khoo A, Mcloughlin B, Cheema S, Weil RS, Lambert C, Manji H,
et al. Postinfectious brainstem encephalitis associated with SARS-
CoV-2. J Neurol Neurosurg Psychiatry 2020; doi: 10.1136/jnnp-
2020-323816.
BRAIN 2020: 143; 3104–3120 | 3119
Kim JE, Heo JH, Kim HO, Song SH, Park SS, Park TH, et al.
Neurological complications during treatment of middle east respira-
tory syndrome. J Clin Neurol 2017; 13: 227–33.
Kremer S, Lersy F, de Sèze J, Ferré J-C, Maamar A, Carsin-Nicol B,
et al. Brain MRI findings in severe COVID-19: a retrospective obser-
vational study. Radiology 2020; 78: 202222.
Mahammedi A, Saba L, Vagal A, Leali M, Rossi A, Gaskill M, et al.
Imaging in neurological disease of hospitalized COVID-19 patients:
An Italian multicenter retrospective observational study. Radiology
2020; 201933.
Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic mani-
festations of hospitalized patients with coronavirus disease 2019 in
Wuhan, China. JAMA Neurol 2020; 77: 683–90.
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson
JJ. COVID-19: consider cytokine storm syndromes and immunosup-
pression. Lancet 2020; 395: 1033–4.
Downloaded from https://academic.oup.com/brain/article/143/10/3104/5868408 by guest on 30 July 2021
Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J,
et al. A first case of meningitis/encephalitis associated with SARS-
Coronavirus-2. Int J Infect Dis 2020; 94: 55–8.
Office for National Statistics. 2019. Estimates of the population for
the UK, England and Wales, Scotland and Northern Ireland.
Available at: https://www.ons.gov.uk/peoplepopulationandcommun
ity/populationandmigration/populationestimates/datasets/population
estimatesforukenglandandwalesscotlandandnorthernireland.
Pohl D, Alper G, Van Haren K, Kornberg AJ, Lucchinetti CF,
Tenembaum S, et al. Acute disseminated encephalomyelitis: updates
on an inflammatory CNS syndrome. Neurology 2016; 87: S38–45.
Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B.
COVID-19-associated acutehemorrhagic necrotizing encephalop-
athy: CT and MRI features. Radiology 2020: 201187. doi: 10.1148/
radiol.2020201187.
Price CC, Altice FL, Shyr Y, Koff A, Pischel L, Goshua G, et al.
Tocilizumab treatment for Cytokine Release Syndrome in hospital-
ized COVID-19 patients: survival and clinical outcomes. Chest
2020; doi: 10.1016/j.chest.2020.06.006.
Rábano-Suárez P, Bermejo-Guerrero L, Méndez-Guerrero A, Parra-
Serrano J, Toledo-Alfocea D, Sánchez-Tejerina D, et al. Generalized
myoclonus in COVID-19. Neurology 2020; doi: 10.1212/WNL.
0000000000009829.
Reichard RR, Kashani KB, Boire NA, Constantopoulos E, Guo Y,
Lucchinetti CF. Neuropathology of COVID-19: a spectrum of vascu-
lar and acute disseminated encephalomyelitis (ADEM)-like path-
ology. Acta Neuropathol 2020; 140: 1–6.
Riollano-Cruz M, Akkoyun E, Briceno-Brito E, Kowalsky S, Posada R,
Sordillo E M, et al. Multisystem Inflammatory Syndrome in
Children (MIS-C) Related to COVID-19: A New York City
Experience. J Med Virol 2020; doi:10.1002/jmv.26224.
Rivas-Garcı́a S, Bernal J, Bachiller-Corral J. Rhabdomyolysis as the
main manifestation of coronavirus disease 2019. Rheumatology
2020; 59: 2174–76.
Rogers JP, Chesney E, Oliver D, Pollak TA, McGuire P, Fusar-Poli P,
et al. Psychiatric and neuropsychiatric presentations associated with
severe coronavirus infections: a systematic review and meta-analysis
with comparison to the COVID-19 pandemic. Lancet Psychiatry
2020; 7: 611–27.
Solomon T, Michael BD, Smith PE, Sanderson F, Davies NWS, Hart
IJ, et al. Management of suspected viral encephalitis in adults –
Association of British Neurologists and British Infection Association
National Guidelines. J Infect 2012; 64: 347–73.
Starkey J, Kobayashi N, Numaguchi Y, Moritani T. Cytotoxic lesions
of the corpus callosum that show restricted diffusion: mechanisms,
causes, and manifestations. Radiographics 2017; 37: 562–76.
Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are
associated with poor prognosis in patients with novel coronavirus
pneumonia. J Thromb Haemost 2020; 18: 844–7.
Toscano G, Palmerini F, Ravaglia S, Ruiz L, Invernizzi P, Cuzzoni
MG, et al. Guillain–Barré syndrome associated with SARS-CoV-2.
N Engl J Med 2020; 382: 2574–6.
3120 | BRAIN 2020: 143; 3104–3120
Tsai LK, Hsieh ST, Chang YC. Neurological manifestations
in severe acute respiratory syndrome. Acta Neurol 2005; 14:
113–9.
Umapathi T, Kor AC, Venketasubramanian N, Lim CCT, Pang BC,
Yeo TT, et al. Large artery ischaemic stroke in severe acute respira-
tory syndrome (SARS). J Neurol 2004; 251: 1227–31.
Varatharaj A, Thomas N, Ellul MA, Davies NWS, Pollak TA, Tenorio
EL, et al. Neurological and neuropsychiatric complications of
COVID-19 in 153 patients: a UK-wide surveillance study. Lancet
Psychiatry 2020; S2215-0366(20)30287-X. doi: 10.1016/S2215-
0366(20)30287-X.
Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R,
Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in
COVID-19. Lancet 2020; 395: 1417–8.
von Weyhern CH, Kaufmann I, Neff F, Kremer M. Early evidence of
pronounced brain involvement in fatal COVID-19 outcomes. Lancet
2020; 395: e109.
Willison HJ, Jacobs BC, van Doorn PA. Guillain-Barré syndrome.
Lancet 2016; 388: 717–27.
R. W. Paterson et al.
Wilson AJ, Troy-Barnes E, Subhan M, Clark F, Gupta R, Fielding AK,
et al. Successful remission induction therapy with gilteritinib in a pa-
tient with de novo FLT3-mutated acute myeloid leukaemia and se-
vere COVID-19. Br J Haematol 2020; doi:10.1111/bjh.16962.
Wu Z, McGoogan JM. Characteristics of and important lessons from
the Coronavirus Disease 2019 (COVID-19) outbreak in China.
JAMA 2020; 323: 1239–42.
Zambreanu L, Lightbody S, Bhandari M, Hoskote C, Kandil H,
Houlihan CF, et al. A case of limbic encephalitis associated with
asymptomatic COVID-19 infection. J Neurol Neurosurg Psychiatry
2020; doi: 10.1136/jnnp-2020-323839.
Zanin L, Saraceno G, Panciani PP, Renisi G, Signorini L, Migliorati K,
et al. SARS-CoV-2 can induce brain and spine demyelinating lesions.
Acta Neurochir 2020; 162: 1491–4.
Zubair AS, McAlpine LS, Gardin T, Farhadian S, Kuruvilla DE,
Spudich S. Neuropathogenesis and Neurologic manifestations of
Downloaded from https://academic.oup.com/brain/article/143/10/3104/5868408 by guest on 30 July 2021
the coronaviruses in the age of coronavirus disease 2019: a
review. JAMA Neurol 2020; doi: 10.1001/jamaneurol.
2020.2065.